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  • Comparative economic evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in patients with bipolar depression (CEQUEL).

    15 November 2018

    OBJECTIVES: Although not licensed for acute bipolar depression, lamotrigine has evidence for efficacy in trials and its use is recommended in guidelines. So far there had been no prospective health economic evaluation of its use. METHODS: Cost-utility analysis of the CEQUEL trial comparing quetiapine plus lamotrigine versus quetiapine monotherapy (and folic acid versus placebo in an add-on factorial design) for patients with bipolar depression (n=201) from the health and social care perspective. Differences in costs together with quality-adjusted life years (QALYs) between the groups were assessed over 52 weeks using a regression-based approach. RESULTS: Health-related quality of life improved substantially for all randomization groups during follow-up with no significant difference in QALYs between any of the comparisons (mean adjusted QALY difference: lamotrigine vs. placebo -0·001 (95% CI: -0·05 to 0·05), folic acid vs. placebo 0·002 (95% CI: -0·05 to 0·05)). While medication costs in the lamotrigine group were higher than in the placebo group (£647, p<0·001), mental health community/outpatient costs were significantly lower (-£670, p<0·001). Mean total costs were similar in the groups (-£180, p=0·913). CONCLUSIONS: Lamotrigine improved clinical ratings in bipolar depression compared with placebo. This differential effect was not detected using the EQ-5D-3L. The additional cost of lamotrigine was balanced by significant savings in some other medical costs which made its use cost neutral to the health service. Compared to placebo, folic acid produced neither clinical nor significant health economic benefits. The study supports the use of lamotrigine in combination with other drugs to treat bipolar depression. This article is protected by copyright. All rights reserved.

  • Protocol for diaphragm pacing in patients with respiratory muscle weakness due to motor neurone disease (DiPALS): a randomised controlled trial.

    24 October 2018

    BACKGROUND: Motor neurone disease (MND) is a devastating illness which leads to muscle weakness and death, usually within 2-3 years of symptom onset. Respiratory insufficiency is a common cause of morbidity, particularly in later stages of MND and respiratory complications are the leading cause of mortality in MND patients. Non Invasive Ventilation (NIV) is the current standard therapy to manage respiratory insufficiency. Some MND patients however do not tolerate NIV due to a number of issues including mask interface problems and claustrophobia. In those that do tolerate NIV, eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective. The NeuRx RA/4 Diaphragm Pacing System was originally developed for patients with respiratory insufficiency and diaphragm paralysis secondary to stable high spinal cord injuries. The DiPALS study will assess the effect of diaphragm pacing (DP) when used to treat patients with MND and respiratory insufficiency. METHOD/DESIGN: 108 patients will be recruited to the study at 5 sites in the UK. Patients will be randomised to either receive NIV (current standard care) or receive DP in addition to NIV. Study participants will be required to complete outcome measures at 5 follow up time points (2, 3, 6, 9 and 12 months) plus an additional surgery and 1 week post operative visit for those in the DP group. 12 patients (and their carers) from the DP group will also be asked to complete 2 qualitative interviews. DISCUSSION: The primary objective of this trial will be to evaluate the effect of Diaphragm Pacing (DP) on survival over the study duration in patients with MND with respiratory muscle weakness. The project is funded by the National Institute for Health Research, Health Technology Assessment (HTA) Programme (project number 09/55/33) and the Motor Neurone Disease Association and the Henry Smith Charity. TRIAL REGISTRATION: Current controlled trials ISRCTN53817913. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

  • Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study

    24 October 2018

    Background: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. Findings: In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. Interpretation: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. Funding: Full funding sources listed at end of paper (see Acknowledgments). © 2012 Elsevier Ltd.

  • Rasch analysis of the hospital anxiety and depression scale (HADS) for use in motor neurone disease.

    24 October 2018

    BACKGROUND: The Hospital Anxiety and Depression Scale (HADS) is commonly used to assess symptoms of anxiety and depression in motor neurone disease (MND). The measure has never been specifically validated for use within this population, despite questions raised about the scale's validity. This study seeks to analyse the construct validity of the HADS in MND by fitting its data to the Rasch model. METHODS: The scale was administered to 298 patients with MND. Scale assessment included model fit, differential item functioning (DIF), unidimensionality, local dependency and category threshold analysis. RESULTS: Rasch analyses were carried out on the HADS total score as well as depression and anxiety subscales (HADS-T, D and A respectively). After removing one item from both of the seven item scales, it was possible to produce modified HADS-A and HADS-D scales which fit the Rasch model. An 11-item higher-order HADS-T total scale was found to fit the Rasch model following the removal of one further item. CONCLUSION: Our results suggest that a modified HADS-A and HADS-D are unidimensional, free of DIF and have good fit to the Rasch model in this population. As such they are suitable for use in MND clinics or research. The use of the modified HADS-T as a higher-order measure of psychological distress was supported by our data. Revised cut-off points are given for the modified HADS-A and HADS-D subscales.

  • HspB8 mutation causing hereditary distal motor neuropathy impairs lysosomal delivery of autophagosomes

    24 October 2018

    HspB8, a small heat-shock protein implicated in autophagy, is mutated in patients with distal hereditary motor neuropathy type II (dHMNII). Autophagy is essential for maintaining protein homeostasis in the central nervous system, but its role has not been investigated in peripheral motor neurons. We used a novel, multispectral-imaging flow cytometry assay to measure autophagy in cells. This assay revealed that over-expression of wild-type HspB8 in motor neuron-like NSC34 cells led to an increased co-localisation of autophagosomes with the lysosomes. By contrast, over-expression of mutant HspB8 resulted in autophagosomes that co-localised with protein aggregates but failed to co-localise with the lysosomes. A similar impairment of autophagy could also be demonstrated in peripheral blood mononuclear cells from two dHMNII patients with the HspB8 K141E mutation. We conclude that defects in HspB8-mediated autophagy are likely to contribute to dHMNII pathology and their detection in peripheral blood mononuclear cells could be a useful, accessible biomarker for the disease. © 2011 International Society for Neurochemistry.

  • Development of a patient reported outcome measure for fatigue in motor neurone disease: the Neurological Fatigue Index (NFI-MND).

    24 October 2018

    BACKGROUND: The objective of this research was to develop a disease-specific measure for fatigue in patients with motor neurone disease (MND) by generating data that would fit the Rasch measurement model. Fatigue was defined as reversible motor weakness and whole-body tiredness that was predominantly brought on by muscular exertion and was partially relieved by rest. METHODS: Qualitative interviews were undertaken to confirm the suitability of a previously identified set of 52 neurological fatigue items as relevant to patients with MND. Patients were recruited from five U.K. MND clinics. Questionnaires were administered during clinic or by post. A sub-sample of patients completed the questionnaire again after 2-4 weeks to assess test-retest validity. Exploratory factor analyses and Rasch analysis were conducted on the item set. RESULTS: Qualitative interviews with ten MND patients confirmed the suitability of 52 previously identified neurological fatigue items as relevant to patients with MND. 298 patients consented to completing the initial questionnaire including this item set, with an additional 78 patients completing the questionnaire a second time after 4-6 weeks. Exploratory Factor Analysis identified five potential subscales that could be conceptualised as representing: 'Energy', 'Reversible muscular weakness' (shortened to 'Weakness'), 'Concentration', 'Effects of heat' and 'Rest'. Of the original five factors, two factors 'Energy' and 'Weakness' met the expectations of the Rasch model. A higher order fatigue summary scale, consisting of items from the 'Energy' and 'Weakness' subscales, was found to fit the Rasch model and have acceptable unidimensionality. The two scales and the higher order summary scale were shown to fulfil model expectations, including assumptions of unidimensionality, local independency and an absence of differential item functioning. CONCLUSIONS: The Neurological Fatigue Index for MND (NFI-MND) is a simple, easy-to-administer fatigue scale. It consists of an 8-item fatigue summary scale in addition to separate scales for measuring fatigue experienced as reversible muscular weakness and fatigue expressed as feelings of low energy and whole body tiredness. The underlying two factor structure supports the patient concept of fatigue derived from qualitative interviews in this population. All three scales were shown to be reliable and capable of interval level measurement.

  • Oxford Persisting Post-Operative Pain Study

    15 January 2013

    NDA

    The aim of OxPPOPS is to identify the incidence and predictive factors for the development of persistent pain after surgery. We have just finished recruiting a cohort of patients having planned caesarean sections.

  • Cognitive Neurology Research Group

    4 March 2013

    DCN

    We want to understand how - and why - brain function can be disturbed to lead to inattention, poor memory and abnormal decision making. Our aim is to develop new treatments for these conditions across a range of neurological disorders.

  • Neuroanatomy and Cognition Group

    15 January 2013

    DCN

    Our projects study cognitive/psychiatric disorders and comparative evolutionary neuroscience. We are interested in the relationship between brain structure and function in disease, development and aging - particularly related to language and social cognition.

  • Epilepsy Imaging Research Group

    14 February 2013

    FMRIB

    Combining state-of-the-art brain imaging methods, we aim to understand how functional networks in the brain respond and adapt to epilepsy and epilepsy-associated lesions.

  • Clinical Ophthalmology Research Group

    15 January 2013

    NLO

    We are developing gene therapy and stem cell treatments for retinal diseases

  • Retinal Neurobiology and Optogenetics Group

    15 January 2013

    NLO

    Our research focuses on light dependent signalling in the retina and brain, including visual and non-visual light detection. We are also examining novel opsin photopigments and exploring their applications to optogenetics.

  • Retinal Degeneration and Gene Identification

    15 January 2013

    NLO

    Our work involves the identification and characterisation of genes that play a role in the retina, including both visual and non-image forming tasks such as the detection of light for the entrainment of the circadian system.

  • Molecular Neurodegeneration Research Group

    11 March 2014

    DCN

    Our aim is to understand fundamental biological processes that could inform the development of targeted therapies and innovative biomarkers in neurodegenerative and neurogenetic disorders.